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Principal Investigator: Pamela J Bjorkman
Organization: CALIFORNIA INSTITUTE OF TECHNOLOGY
Fiscal Year: 2021
Award: $410,750
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
The rapid mutation rate of HIV-1 results in many thousands of viral strains, thus thwarting current vaccine
efforts. Although HIV-1 infection can be controlled by anti-retroviral therapy (ART), the virus rebounds within
weeks of ART cessation because complete elimination of HIV-1 is prevented by latent viral reservoirs. Broadly
neutralizing antibodies (bNAbs) against the HIV-1 envelope spike (Env) that have been isolated from a subset
of HIV-1–infected donors are protective against HIV-1 infection and can lower the viral load after infection, and
it has been suggested that bNAbs could play a role in eliminating the viral reservoir. However, HIV-1 can
evade even the most potent bNAbs by mutation. Here we seek to engineer bNAbs to be resistant to viral
mutation so they could be used to eliminate viral reservoirs. Our strategy relies upon harnessing avidity effects
to prevent viral resistance to bNAbs at both an individual and population level. We hypothesize that HIV-1
hinders IgGs from using both antigen-binding Fabs to bind bivalently. This is accomplished by the small
number and low density of HIV-1 Env spikes, which prevent most IgGs from inter-spike crosslinking (bivalent
binding between spikes), and the architecture of the Env trimer, which impedes intra-spike crosslinking
(bivalent binding within a spike). We suggested that predominantly monovalent binding expands the range of
HIV-1 mutations permitting Ab evasion, whereas reagents capable of bivalent binding through intra-spike
crosslinking would be more potent across multiple strains of HIV-1. This hypothesis was supported by our
demonstration of up to 100-fold increases in geometric mean potency achieved with our first generation intra-
spike crosslinking reagents (homo- and hetero-diFabs joined by rigid DNA linkers). These results support the
hypothesis that HIV's low spike density contributes to vulnerability of HIV-1 bNAbs to spike mutations and
suggests that the ideal anti-HIV therapeutic for eliminating HIV reservoirs would utilize avidity to achieve intra-
spike crosslinking because this sort of therapeutic would reduce the concentration required for sterilizing
immunity and be resistant to Env mutations. Here we propose to design, produce, and evaluate second
generation intra-spike crosslinking reagents with two improvements: (i) they will contain an IgG Fc to mediate
effector functions and increase the serum half-life, and (ii) the DNA will be replaced by structured protein
linkers. We will also evaluate the effects of Fc substitutions designed to enhance Fc-mediated effector
functions through tighter binding to activating FcγR receptors and improve serum half-life through enhanced
binding to FcRn, including a novel computational design strategy to improve binding to FcRn under conditions
that promote increased IgG half-life. These more potent bNAbs could be used therapeutically at lower
concentrations and thus reduce cost and/or production time, increase the number of patients being treated,
and lower the potential for immunogenicity or other side-effects related to bNAb administration.
Terms: <7S Gamma Globulin><ADCC Assay><AIDS Virus><AIDS/HIV><AIDS/HIV problem><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Anti-Retroviral Agents><Antigenic Determinants><Antiretroviral Agents><Architecture><Assay><Avidity><Bifunctional Reagents><Binding><Binding Determinants><Bioassay><Biologic Assays><Biological Assay><Blood Serum><Cross-Linking Reagents><Crosslinking Reagents><Crystallization><DNA><Deoxyribonucleic Acid><Drug resistance><Drugs><Engineering><Engineering / Architecture><Epitopes><Evolution><Exhibits><FcRn><FcRn neonatal transfer protein><Generations><Genetic Alteration><Genetic Change><Genetic defect><Goals><HIV><HIV Antibodies><HIV-1><HIV-Associated Antibodies><HIV-I><HIV/AIDS><HIV/AIDS problem><HIV1><HTLV-III Antibodies><HTLV-III-LAV Antibodies><Half-Life><Homo><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Antibodies><Human immunodeficiency virus 1><IgG><Immunity><Immunoglobulin G><In Vitro><Individual><Infection><LAV Antibodies><LAV-HTLV-III><Libraries><Linker DNA><Lymphadenopathy-Associated Antibodies><Lymphadenopathy-Associated Virus><Measures><Mediating><Medication><Molecular><Molecular Interaction><Mutation><Nucleosomal Linker><Patients><Persons><Pharmaceutic Preparations><Pharmaceutical Preparations><Play><Population><Predisposition><Production><Public Health><Reagent><Receptor Protein><Research><Resistance><Role><Serum><Structural Protein><Structure><Susceptibility><Therapeutic><Therapeutic Uses><Time><Vaccines><Viral><Viral Burden><Viral Latency><Viral Load><Viral Load result><Viral reservoir><Virion><Virus><Virus Latency><Virus Particle><Virus reservoir><Virus-HIV><anti-retroviral><anti-retroviral therapy><anti-retroviral treatment><antigen binding><antigen bound><antiretroviral><antiretroviral therapy><antiretroviral treatment><base><cost><cross-link><crosslink><density><design><designing><drug resistant><drug/agent><experiment><experimental research><experimental study><genome mutation><immunogenicity><improved><natural antibodies><neonatal Fc receptor><neutralizing antibody><novel><prevent><preventing><receptor><resistance to Drug><resistant><resistant to Drug><side effect><small molecule><social role><synergism><viral rebound><viral resistance><virus rebound><virus resistance>